Conformation-selective ATP-competitive inhibitors control regulatory interactions and noncatalytic functions of mitogen-activated protein kinases.
Conformation-selective ATP-competitive inhibitors control regulatory interactions and noncatalytic functions of mitogen-activated protein kinases.
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DOI：
10.1016/j.chembiol.2014.02.016
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发表时间：
2014-05-22
影响因子：
--
通讯作者：
Maly DJ
中科院分区：
文献类型：
--
作者：
Hari SB;Merritt EA;Maly DJ
大多数有效的蛋白激酶抑制剂通过与ATP竞争来阻断其靶点的磷酸转移酶活性。然而，新出现的证据表明，ATP竞争性抑制剂可以影响激酶的相互作用和功能的方式超越阻断催化活性。在这里，我们表明，稳定的交替ATP结合位点构象的有丝分裂原活化蛋白激酶（MAPK）p38α和Erk2与ATP竞争性抑制剂的差异，在某些情况下分歧，调节这些激酶的能力，与上游激活剂和失活磷酸酶。构象选择性配体也能够调节Erk2的变构激活MAPK磷酸酶DUSP6的能力，突出了ATP竞争性配体如何控制非催化激酶功能。总体而言，这些研究强调了ATP结合和MAPK的调节位点之间的关系，并提供了ATP竞争性配体如何被设计为对蛋白激酶功能进行分级控制的见解。
Most potent protein kinase inhibitors act by competing with ATP to block the phosphotransferase activity of their targets. However, emerging evidence demonstrates that ATP-competitive inhibitors can affect kinase interactions and functions in ways beyond blocking catalytic activity. Here, we show that stabilizing alternative ATP-binding site conformations of the mitogen-activated protein kinases (MAPKs) p38α and Erk2 with ATP-competitive inhibitors differentially, and in some cases divergently, modulates the abilities of these kinases to interact with upstream activators and deactivating phosphatases. Conformation-selective ligands are also able to modulate Erk2’s ability to allosterically activate the MAPK phosphatase DUSP6, highlighting how ATP-competitive ligands can control noncatalytic kinase functions. Overall, these studies underscore the relationship between the ATP-binding and regulatory sites of MAPKs and provide insight into how ATP-competitive ligands can be designed to confer graded control over protein kinase function.
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影响因子：
2.9
作者：
Sullivan, JE;Holdgate, GA;Ward, WHJ
通讯作者：
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通讯作者：
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DOI：
10.1073/pnas.1109879108
发表时间：
2011-11-15
影响因子：
11.1
作者：
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通讯作者：
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